Genotype-phenotype correlation in clubfoot (talipes equinovarus).

Abstract

Clubfoot (talipes equinovarus) is a congenital malformation affecting muscles, bones, connective tissue and vascular or neurological structures in limbs. It has a complex aetiology, both genetic and environmental. To date, the most important findings in clubfoot genetics involve <i>PITX1</i> variants, which were linked to clubfoot phenotype in mice and humans. Additionally, copy number variations encompassing <i>TBX4</i> or single nucleotide variants in <i>HOXC11</i>, the molecular targets of the PITX1 transcription factor, were linked to the clubfoot phenotype. In general, genes of cytoskeleton and muscle contractile apparatus, as well as components of the extracellular matrix and connective tissue, are frequently linked with clubfoot aetiology. Last but not least, an equally important element, that brings us closer to a better understanding of the clubfoot genotype/phenotype correlation, are studies on the two known animal models of clubfoot-the <i>pma</i> or <i>EphA4</i> mice. This review will summarise the current state of knowledge of the molecular basis of this congenital malformation.